Regulation of Tumor-Associated Myeloid Cell Activity by CBP/EP300 Bromodomain Modulation of H3K27 Acetylation
Summary: Myeloid-derived suppressor cells (MDSCs) are found in most cancer malignancies and support tumorigenesis by suppressing immunity and promoting tumor growth. Here we identify the bromodomain (BRD) of CBP/EP300 as a critical regulator of H3K27 acetylation (H3K27ac) in MDSCs across promoters a...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-04-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124719303158 |
| _version_ | 1818290418301796352 |
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| author | Denise E. de Almeida Nagata Eugene Y. Chiang Suchit Jhunjhunwala Patrick Caplazi Vidhyalakshmi Arumugam Zora Modrusan Emily Chan Mark Merchant Lingyan Jin David Arnott F. Anthony Romero Steven Magnuson Karen E. Gascoigne Jane L. Grogan |
| author_facet | Denise E. de Almeida Nagata Eugene Y. Chiang Suchit Jhunjhunwala Patrick Caplazi Vidhyalakshmi Arumugam Zora Modrusan Emily Chan Mark Merchant Lingyan Jin David Arnott F. Anthony Romero Steven Magnuson Karen E. Gascoigne Jane L. Grogan |
| author_sort | Denise E. de Almeida Nagata |
| collection | DOAJ |
| description | Summary: Myeloid-derived suppressor cells (MDSCs) are found in most cancer malignancies and support tumorigenesis by suppressing immunity and promoting tumor growth. Here we identify the bromodomain (BRD) of CBP/EP300 as a critical regulator of H3K27 acetylation (H3K27ac) in MDSCs across promoters and enhancers of pro-tumorigenic target genes. In preclinical tumor models, in vivo administration of a CBP/EP300-BRD inhibitor (CBP/EP300-BRDi) alters intratumoral MDSCs and attenuates established tumor growth in immunocompetent tumor-bearing mice, as well as in MDSC-dependent xenograft models. Inhibition of CBP/EP300-BRD redirects tumor-associated MDSCs from a suppressive to an inflammatory phenotype through downregulation of STAT pathway-related genes and inhibition of Arg1 and iNOS. Similarly, CBP/EP300-BRDi decreases differentiation and suppressive function of human MDSCs in vitro. Our findings uncover a role of CBP/EP300-BRD in intratumoral MDSCs that may be targeted therapeutically to boost anti-tumor immunity. : de Almeida Nagata et al. investigate the regulation of intratumoral myeloid-derived suppressor cells (MDSCs) by the CBP/EP300 bromodomain (BRD). By modulating H3K27 acetylation of STAT-associated genes, CBP/EP300-BRD controls MDSC function. Inhibition of the BRD reduces tumor growth in pre-clinical models, suggesting that CBP/EP300-BRD may be targeted to boost anti-tumor immunity. Keywords: CBP, EP300, H3K27ac, bromodomain, myeloid-derived suppressive cells, tumors |
| first_indexed | 2024-12-13T02:27:51Z |
| format | Article |
| id | doaj.art-59bed4a4121e435abacf7f0ac7ad65fe |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-13T02:27:51Z |
| publishDate | 2019-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-59bed4a4121e435abacf7f0ac7ad65fe2022-12-22T00:02:34ZengElsevierCell Reports2211-12472019-04-01271269281.e4Regulation of Tumor-Associated Myeloid Cell Activity by CBP/EP300 Bromodomain Modulation of H3K27 AcetylationDenise E. de Almeida Nagata0Eugene Y. Chiang1Suchit Jhunjhunwala2Patrick Caplazi3Vidhyalakshmi Arumugam4Zora Modrusan5Emily Chan6Mark Merchant7Lingyan Jin8David Arnott9F. Anthony Romero10Steven Magnuson11Karen E. Gascoigne12Jane L. Grogan13Department of Cancer Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USADepartment of Cancer Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USADepartment of Bioinformatics, Genentech, 1 DNA Way, South San Francisco, CA 94080, USADepartment of Pathology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USADepartment of Cancer Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USADepartment of Micro Array Lab, Genentech, 1 DNA Way, South San Francisco, CA 94080, USADepartment of Translational Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USADepartment of Translational Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USADepartment of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USADepartment of Technology, Proteomics & Biological Resources, Genentech, 1 DNA Way, South San Francisco, CA 94080, USADiscovery Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USADiscovery Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USADepartment of Discovery Oncology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USADepartment of Cancer Immunology, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA; Corresponding authorSummary: Myeloid-derived suppressor cells (MDSCs) are found in most cancer malignancies and support tumorigenesis by suppressing immunity and promoting tumor growth. Here we identify the bromodomain (BRD) of CBP/EP300 as a critical regulator of H3K27 acetylation (H3K27ac) in MDSCs across promoters and enhancers of pro-tumorigenic target genes. In preclinical tumor models, in vivo administration of a CBP/EP300-BRD inhibitor (CBP/EP300-BRDi) alters intratumoral MDSCs and attenuates established tumor growth in immunocompetent tumor-bearing mice, as well as in MDSC-dependent xenograft models. Inhibition of CBP/EP300-BRD redirects tumor-associated MDSCs from a suppressive to an inflammatory phenotype through downregulation of STAT pathway-related genes and inhibition of Arg1 and iNOS. Similarly, CBP/EP300-BRDi decreases differentiation and suppressive function of human MDSCs in vitro. Our findings uncover a role of CBP/EP300-BRD in intratumoral MDSCs that may be targeted therapeutically to boost anti-tumor immunity. : de Almeida Nagata et al. investigate the regulation of intratumoral myeloid-derived suppressor cells (MDSCs) by the CBP/EP300 bromodomain (BRD). By modulating H3K27 acetylation of STAT-associated genes, CBP/EP300-BRD controls MDSC function. Inhibition of the BRD reduces tumor growth in pre-clinical models, suggesting that CBP/EP300-BRD may be targeted to boost anti-tumor immunity. Keywords: CBP, EP300, H3K27ac, bromodomain, myeloid-derived suppressive cells, tumorshttp://www.sciencedirect.com/science/article/pii/S2211124719303158 |
| spellingShingle | Denise E. de Almeida Nagata Eugene Y. Chiang Suchit Jhunjhunwala Patrick Caplazi Vidhyalakshmi Arumugam Zora Modrusan Emily Chan Mark Merchant Lingyan Jin David Arnott F. Anthony Romero Steven Magnuson Karen E. Gascoigne Jane L. Grogan Regulation of Tumor-Associated Myeloid Cell Activity by CBP/EP300 Bromodomain Modulation of H3K27 Acetylation Cell Reports |
| title | Regulation of Tumor-Associated Myeloid Cell Activity by CBP/EP300 Bromodomain Modulation of H3K27 Acetylation |
| title_full | Regulation of Tumor-Associated Myeloid Cell Activity by CBP/EP300 Bromodomain Modulation of H3K27 Acetylation |
| title_fullStr | Regulation of Tumor-Associated Myeloid Cell Activity by CBP/EP300 Bromodomain Modulation of H3K27 Acetylation |
| title_full_unstemmed | Regulation of Tumor-Associated Myeloid Cell Activity by CBP/EP300 Bromodomain Modulation of H3K27 Acetylation |
| title_short | Regulation of Tumor-Associated Myeloid Cell Activity by CBP/EP300 Bromodomain Modulation of H3K27 Acetylation |
| title_sort | regulation of tumor associated myeloid cell activity by cbp ep300 bromodomain modulation of h3k27 acetylation |
| url | http://www.sciencedirect.com/science/article/pii/S2211124719303158 |
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